Supplementary Material for: Diabetes, Smoking, Alcohol Use, and Family History of Cancer as Risk Factors for Pancreatic Neuroendocrine Tumors: A Systematic Review and Meta-Analysis

<b><i>Background and Aims:</i></b> Risk factors for pancreatic neuroendocrine tumors (PNETs) are not well understood. The aim of this systematic review was to assess if diabetes mellitus, smoking, alcohol use, and family history of cancer are risk factors for PNETs. <b><i>Methods:</i></b> MEDLINE and abstracts from the European and North American Neuroendocrine Tumor Societies (ENETS and NANETS) were searched for studies published until October 2013. Eligible studies were selected according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. <b><i>Results:</i></b> Five studies evaluating 4 individual populations were included (study accrual period 2000-2011) into the meta-analysis, involving 827 cases (range 160-309 per study) and 2,407 controls (range 233-924 per study). All studies had a case-control design and described regional series. The pooled adjusted odds ratio was 2.74 (95% CI: 1.63-4.62; p < 0.01; I<sup>2</sup> = 60.4%) for history of diabetes, 1.21 (95% CI: 0.92-1.58; p = 0.18; I<sup>2</sup> = 45.8%) for ever smoking, 1.37 (95% CI: 0.99-1.91; p = 0.06; I<sup>2</sup> = 0.0%) for heavy smoking, 1.09 (95% CI: 0.64-1.85; p = 0.75; I<sup>2</sup> = 85.2%) for ever alcohol use, 2.72 (95% CI: 1.25-5.91; p = 0.01; I<sup>2</sup> = 57.8%) for heavy alcohol use, and 2.16 (95% CI: 1.64-2.85; p < 0.01; I<sup>2</sup> = 0.0%) for first-degree family history of cancer. <b><i>Conclusions:</i></b> Diabetes mellitus and first-degree family history of cancer are associated with an increased risk of sporadic PNET. There was also a trend for diagnosis of sporadic PNET associated with heavy smoking. Alcohol use may be a risk factor for PNET, but there was considerable heterogeneity in the meta-analysis. These results suggest the need for a larger, homogeneous, international study for the clarification of risk factors for the occurrence of PNET.